Dengue and yellow fever viruses (YFV) cause some of the most important mosquito-borne diseases with extensive morbidity and mortality around the world. Yellow fever virus causes an acute hemorrhagic fever complicated by hepatitis, renal failure, coagulation abnormalities, and in severe cases, death. Currently, there are large outbreaks of yellow fever in countries in West Africa and South America. A live, attenuated yellow fever vaccine (YFV-17D) has been in use since the 1930s and is highly efficacious in preventing yellow fever. It provides long-term immunity for over 30 years and up to a life time. The FDA licensed yellow fever vaccine allows us an opportunity to study the underlying immunological mechanisms that confer long term protective immunity in humans. Dengue virus infection is the most prevalent mosquito-borne infectious disease in the world. There are four distinct, but closely related serotypes of dengue virus (DEN-1, DEN-2, DEN-3 and DEN-4). Recovery from infection by one serotype does not provide protective immunity to another. The incidence of dengue fever and a more severe form of dengue known as dengue hemorrhagic fever have increased dramatically worldwide with 40% of world?s population in over 100 countries being at risk. Understanding protective immune responses and long-term immunity in natural infection is key for vaccine development. Knowledge gained from these studies will inform the immune responses needed for a safe and effective dengue vaccine. In the past and current CCHI funding cycles, the Clinical Core has been a vital component of the Emory CCHI program and continues to support the CCHI scientific agenda for over 10 years. The Core has three units: (1) Hope Clinic Unit at Emory University, Atlanta, GA (2) Dengue Clinical Unit at Siriraj Hospital of Mahidol University, in Bangkok, Thailand; (3) Statistical Unit at Emory University, Atlanta, GA. In this proposal, we plan to continue to perform novel innate and cellular immunity studies along with state-of-the art single cell and integrated genomics to advance our fundamental understanding of immune memory, innate immunity, immune senescence. The Hope Clinic Unit will continue studies with the YFV vaccine clinical studies to provide appropriate specimens for Projects 1, 2 and 3. The Dengue Clinical Unit at Siriraj Hospital in Bangkok, Thailand will continue with the dengue studies from acutely infected children and adults. The innate immunity and immune senescence work will continue at Stanford University.